The present invention relates to a medicament for the treatment of diseases related to neoangenesis.
Angiogenesis is defined as the formation of new blood vessels by outgrowth of endothelial cells from pre-existing vessels. During this process, endothelial cells degrade the underlying basement membrane, proliferate, migrate into neighboring tissue, and assemble into tubes. Finally, tube-to-tube connections are made and blood flow is established. The ability of mature tissues to adapt to changing demands requires both soluble factors like hypoxia inducible Factor (HIF) and Vascular endothelial factor (VEGF) and cell-cell as well as cell-matrix interactions.
VEGF was originally described as factor causing substantial vascular leakage and was named Vascular Permeability Factor (VPF). On account of its mitogenic effect in endothelial cells, the same protein was later renamed Vascular Endothelial Growth Factor (VEGF).
VEGF increases the permeability of the micro-vascular bed, thus promoting fluid and protein leakage from blood vessels. This results in the development of oedemas, wound fluid and seromas (e.g. after surgery), effusions (e.g. in chronic inflammatory diseases) and ascites (e.g. in cancer). VEGF is 10,000 times more potent than histamine in induction of vascular permeability.
Furthermore, VEGF is one of the most potent stimulators of endothelial cell proliferation. Finally, it stimulates the formation of capillaries from endothelial cells, thus promoting the cascade of events necessary for angiogenesis. Neoangiogenesis, the growth of new capillaries from pre-existing vessels in newly formed tissues or even deposits (like plaques etc.), contributes to the development and progression of a variety of pathological conditions. Under physiological conditions, angiogenesis is a tightly regulated process. In pathological conditions like cancer, rheumatoid arthritis, endometriosis, psoriasis or ocular neovascularisation this process is considerably enhanced and dysfunctional.
Growing evidence suggest that anti-angiogenic drugs will improve future therapies of diseases like cancer, rheumatoid arthritis, psoriasis and ocular neovascularisation and others. In vivo experiments demonstrated that hypoxia (e.g. in regions close to tumour necroses) is capable of inducing the expression of both VEGF and VEGF receptors (VEGFR-1) in different types of cells. Hypoxia causes the expression of Hypoxia-inducible factor-1 (HIF-1). Subsequently, HIF-1 complexes accumulate in the cell nucleus, bind to the HIF-1 binding site of the DNA, and initiate resp. upregulate transcription of VEGF-mRNA triggering an angiogenic switch that may cause adjacent blood vessels to sprout into the hypoxic tissue. Furthermore, VEGF expression can be induced/upregulated by various proinflammatory cytokines as it has been demonstrated in various models of chronic inflammation like psoriasis or rheumatoid arthritis.
VEGF can be removed from the circulation via the Alpha2-macroglobulin (a2M) pathway by protease-activated a2M. The a2M-protease complex is capable of binding VEGF in a vault at the surface. The resulting a2M-enzyme-VEGF complex is bound to the LRP receptor (low-density lipoprotein receptor-related protein receptor) expressed on the surface of cells like macrophages and endothelial cells, phagocytosed and destroyed. Oral Therapy with proteolytic Enzymes increases the number of activated a2M molecules thus elevating the cytokine/growth factor destroying capacity of the organisms (Desser L et al. Cancer Chemother Pharmacol Suppl (2001) 47:S10-515; Lauer D et al. Cancer Chemother Pharmacol Suppl (2001) 47:S4-S9).
Recently, several therapeutical approaches using VEGF receptor blockers or antibodies against VEGF have been proposed for the treatment of diseases involving increased angiogenesis, mainly cancer, but also for diseases involving angiogenesis in the eye such as macular degeneration.
Ocular neovascularisation or neoangiogenesis has been implicated as the most common cause of blindness and underlies the pathology of approximately 20 different eye diseases. E.g. in diabetes, new capillaries formed in the retina invade the vitreous humor, causing bleeding and blindness.
WO 2005/110453 relates to the use of human wild-type and mutein MT-SP1 proteases for cleaving VEGF and VEGF receptor. Such a cleaving leads to a reduction in angiogenesis and may thus be used to treat pathologies associated with angiogenesis.
JP 60112720 A relates to the use of papain and citric acid to treat diseases which are not associated with angiogenesis (e.g. glaucoma).
In the WO 2004/046199 the use of chondroitin sulfate to treat eye diseases is disclosed.
WO 2005/056784 relates to the use of nattokinase to treat diabetes.
In the SU 1342500 the use of papain to treat eye diseases like glaucoma is described.
U.S. Pat. No. 6,103,756 relates to a composition comprising antoxidant and flavonoids which may be used to treat eye disorders.